Synthesis and dopamine transporter binding of 2′-substituted cocaine analogs

A series of 2'-substituted cocaine analogs (4-8) was synthesized and evaluated in an in vitro dopamine transporter (DAT) system. Compounds 4-7 were prepared by esterifying the 3 beta-hydroxyl group of ecgonine methyl ester (3) using the appropriate acid chloride in the presence of NEt3 and benzene. Compound 3 was obtained from cocaine (1) by hydrolysis using 1N HCl to afford ecgonine HCl which was subjected to acid catalyzed esterification using MeOH saturated with HCl gas. Compound 8 was obtained from 5 by selective trans-esterification with MeOH and HCl gas. The binding affinities of these compounds were determined at DAT for the displacement of [H-3]WIN-35428 (2). The 2'-substituted acetoxy and hydroxy analogs exhibited high binding potency for the DAT compared to cocaine (3.5- and 10-fold respectively).